Project Summary The nature of selective neuronal vulnerability represents a fundamental question in the pathophysiology of Alzheimer?s disease (AD). b-amyloid (Ab) is a hallmark pathology of AD, yet some cell types are very resistant to Ab toxicity, and about 30% of elderly individuals remain cognitively normal despite Ab accumulation. Differential gene expression among cell types, and among individuals likely contributes to selective vulnerability or resilience. Discoveries from our laboratories provide novel, compelling examples of disease dependent, cell type specific gene expression in AD. Using massively-parallel droplet based single nuclei transcriptomic sequencing (snRNAseq), we discovered that RBFOX1, a RNA binding protein involved in stress granule, and together with two previously known AD genes, ApoE and GFAP are selectively upregulated in astrocytes in AD brain. This proposal will use snRNAseq to elucidate cell type selective transcriptomes in entorhinal cortex from AD and control cases. This work will lead to fundamental advances in our knowledge of cell type specific genes regulating the pathophysiology of neurons and glial cells in AD.